High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience

Simple Summary Undifferentiated pleomorphic sarcomas (UPSs) represent 10–20% of all soft tissue sarcomas (STSs) and have quickly emerged as one of the more immune-sensitive types. There are few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and those with other high-grade pleomorphic STSs. This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center intended to describe the efficacy and toxicity of ICB in this particular group of patients. We find that our outcomes are comparable to those in the published literature and pose a question regarding the need to further evaluate the optimal sequencing of radiotherapy and prior lines of systemic therapy. Abstract Background: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. Purpose: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. Methods: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. Results: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. Conclusions: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.


Introduction
Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas (STSs), representing 10-20% of all STSs [1,2].Morphologically, UPS consists of pleomorphic spindle cells with no specific line of differentiation [3] and is a specific entity distinct from other high-grade pleomorphic sarcomas not otherwise specified [4,5].The mainstay of advanced/metastatic treatment for STSs in general and UPSs in particular consists of systemic therapies, with doxorubicin-based [6,7] and gemcitabinebased treatments used as front-line treatment, with a median progression-free survival (PFS) of around 6 months and a median overall survival (OS) of around 18-20 months [2,[8][9][10][11][12].
UPS has quickly emerged as one of the more immune-sensitive types of STS, which was identified during the first immune checkpoint blockade (ICB) clinical trials in patients with advanced and pretreated STS with an objective response rate (ORR) of 20-40% and a median PFS of 3 months [13][14][15][16][17][18][19], whereas other types of sarcomas such as leiomyosarcomas or synovial sarcomas have an ORR < 10% with ICB.Building upon this, several clinical trials have looked at the role of combination therapies with ICB across several STS types, including UPSs, and demonstrated increased efficacy of combination treatments over single agents [20][21][22][23].These combinations are now moving to the earlier setting including first-line advanced [19] and peri-operative settings [24].
While there is an increasing number of ICB-based clinical trials with UPS patients, few real-world data on the use of ICB in UPS patients and other high-grade pleomorphic STS patients are available.Thus, our aim was to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution.

Study Design
This is a retrospective, observational study of all patients with high-grade pleomorphic sarcomas treated at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023 with anti-PDL1 and anti-CTLA4 ICB.Patients were identified through our MD Anderson Cancer Center's pharmacy database using the following molecule names: ipilimumab, nivolumab, durvalumab, tremelimumab, atezolizumab, and pembrolizumab.Patients receiving ICB outside of our institution were not identified and, thus, not included.Patients with at least one month of follow-up after initiation of ICB were included.To keep a homogeneous cohort, patients with localized disease receiving ICB treatment in the neoadjuvant setting were excluded.Patients included in trials for which results are not yet published were excluded.
Clinical variables recorded included demographic characteristics such as sex, age, BMI, race and ethnicity, and European Cooperative Oncology Group (ECOG) performance status at initiation of ICB treatment.Disease-associated variables collected included the site of the primary tumor, stage at ICB treatment (locally recurrent/advanced or metastatic), location of metastasis if present, tumor size (biggest dimension, evaluated per RECIST criteria) [25] at ICB, and histologic type.Prior treatment modalities were recorded, including systemic therapies, radiation therapy (RT), and surgical resections.For patients with multiple surgical resections, treatment modalities (chemotherapy regimens and RT) between each surgical resection and any eventual recurrence were recorded.Variables pertaining to ICB

Patient Characteristics
Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included in this study.Patient demographics and disease characteristics are outlined in Table 1.The median age of the patients at the time of initiation of ICB treatment was 52 years (range: 22-79), and 66% were male (n = 24/36).Most patients had an ECOG performance status of 1 (n = 23; 64%).The median body mass index (BMI) at the time of ICB treatment was 30.3 (range: 20-52).The disease histology was UPS in 72% of patients (n = 26/36).The median size of the biggest tumor at the start of ICB treatment was 6 cm (range: 1.3-25).The site of the primary tumor was divided between extremities (n = 15; 42%), trunk (n = 15; 42%), and other (n = 6; 16%), respectively.Lung and liver metastases were seen in 72% (n = 26) and 11% (n = 4) of patients, respectively.

Responses to ICB
The best response of patients to treatment was progression of disease (n = 21; 58%), stable disease (n = 9; 25%), partial response (n = 2; 6%), or complete response (n = 1; 3%).One patient with UPS achieved CR after seven cycles of pembrolizumab, having received prior RT (56 months prior to ICB) and one prior line of gemcitabine-based systemic therapy.Three patients did not have an evaluable response due to logistical issues related to insurance coverage that prevented imaging at MD Anderson after ICB start.Responses are illustrated in the waterfall plot shown in Figure 1.

Responses to ICB
The best response of patients to treatment was progression of disease (n stable disease (n = 9; 25%), partial response (n = 2; 6%), or complete response One patient with UPS achieved CR after seven cycles of pembrolizumab, havi prior RT (56 months prior to ICB) and one prior line of gemcitabine-base therapy.Three patients did not have an evaluable response due to logistical is to insurance coverage that prevented imaging at MD Anderson after ICB start are illustrated in the waterfall plot shown in Figure 1.In the 33 patients with an evaluable response by imaging, the ORR wa 3/33) and the CBR was 30.3% (n = 10/33).Table 2 shows the response rates acco studied clinical characteristics.Previous RT, sex, BMI, histology, presence of l metastasis, number of previous lines of systemic therapy, and type of ICB tre In the 33 patients with an evaluable response by imaging, the ORR was 9.1% (n = 3/33) and the CBR was 30.3% (n = 10/33).Table 2 shows the response rates according to the studied clinical characteristics.Previous RT, sex, BMI, histology, presence of liver or lung metastasis, number of previous lines of systemic therapy, and type of ICB treatment did not statistically significantly affect CBR.None of the aforementioned characteristics had a significant impact on ORR either.

Liver Metastasis
Yes No

Progression-Free Survival with ICB
With a median follow-up time of 8.8 months, the median PFS was 2.9 months, as seen in Figure 2A.The 3-month PFS and 6-month PFS were 46% and 32%, respectively.
The median PFS was 2.9 months and 3.8 months in the UPS group and in the other high-grade pleomorphic sarcoma group, respectively.
In univariate analyses of PFS (Table 3; Figure 3), ICB combination was associated with significantly shorter PFS (combination: 2.3 months vs. no combination 9.2 months, p = 0.021) while previous RT, sex, histology, age, presence of liver or lung metastasis, and number of previous lines of systemic therapy did not.Sarcoma histology (UPSs vs. other high-grade pleomorphic sarcomas) did not have a statistically significant impact on PFS (p = 0.93) (Figure 4A).The previous number of systemic lines of therapies (>2 vs. 1 or 2) was not significantly associated with PFS despite an HR of 2.06 (p = 0.053).Likewise, previous RT was not significantly associated with PFS despite an HR of 0.49 (p = 0.054).
The best response to ICB treatment was significantly associated with PFS (p = 0.0012) (Figure 5A): the median PFS was 40.7 months and 5.6 months in patients whose tumors responded (PR/CR) and stabilized (SD) per RECIST 1.1, respectively, compared to 2.2 months in non-responders.The median PFS was 2.9 months and 3.8 months in the UPS group and in the other high-grade pleomorphic sarcoma group, respectively.
In univariate analyses of PFS (Table 3; Figure 3), ICB combination was associated with significantly shorter PFS (combination: 2.3 months vs. no combination 9.2 months, p = 0.021) while previous RT, sex, histology, age, presence of liver or lung metastasis, and number of previous lines of systemic therapy did not.Sarcoma histology (UPSs vs. other high-grade pleomorphic sarcomas) did not have a statistically significant impact on PFS (p = 0.93) (Figure 4A).The previous number of systemic lines of therapies (>2 vs. 1 or 2) was not significantly associated with PFS despite an HR of 2.06 (p = 0.053).Likewise, previous RT was not significantly associated with PFS despite an HR of 0.49 (p = 0.054).In the multivariate analysis including RT prior to ICB treatment, the number of previous systemic therapies (>2 vs. 1 or 2), and the type of ICB treatment (standalone vs. combination), only previous RT and the type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0019 and p = 0.036, respectively, Table 3).There was no significant difference in PFS (p = 0.52) between patients receiving peri-operative RT and patients receiving RT with palliative intent in the metastatic setting (Supplementary Figure S1).The best response to ICB treatment was significantly associated with PFS (p = 0.0012) (Figure 5A): the median PFS was 40.7 months and 5.6 months in patients whose tumors responded (PR/CR) and stabilized (SD) per RECIST 1.1, respectively, compared to 2.2 months in non-responders.
In the multivariate analysis including RT prior to ICB treatment, the number of previous systemic therapies (>2 vs. 1 or 2), and the type of ICB treatment (standalone vs. combination), only previous RT and the type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0019 and p = 0.036, respectively, Table 3).There was no significant difference in PFS (p = 0.52) between patients receiving peri-operative RT and patients receiving RT with palliative intent in the metastatic setting (Supplementary Figure S1).

Overall Survival with ICB
The median OS was 12.9 months in the whole cohort (Figure 2B).The 12-month OS and 24-month OS rates were 53% and 29%, respectively.
The median OS was 12.9 months and 15 months in the UPS group and in the other high-grade pleomorphic group, respectively.
In the univariate analyses for OS, previous RT had a statistically significant impact on OS (HR = 0.44, previous RT 7.9 months vs. no previous RT 17.5 months, p = 0.047, Supplementary Table S1 and Supplementary Figure S2) while age, race and ethnicity, sex, histology, presence of liver or lung metastasis, number of previous lines of systemic therapy (Supplementary Figure S3), and type of ICB combination (Supplementary Figure S4) did not.Sarcoma histology (UPSs vs. other pleomorphic sarcomas) did not have a statistically significant impact on OS (p = 0.90) (Figure 4B).
The best response to ICB treatment per RECIST1.1 significantly impacted OS (p = 0.011) (Figure 5B): the median OS was not attained and 18.6 months in patients whose tumors responded and stabilized per RECIST 1.1, respectively.

Previous Radiation Therapy
Due to the results on the impact of previous radiation therapy, we performed additional analyses to compare patients who had had previous RT and those who did not.While no significant difference was found between these two groups, patients who had

Overall Survival with ICB
The median OS was 12.9 months in the whole cohort (Figure 2B).The 12-month OS and 24-month OS rates were 53% and 29%, respectively.
The median OS was 12.9 months and 15 months in the UPS group and in the other high-grade pleomorphic group, respectively.
In the univariate analyses for OS, previous RT had a statistically significant impact on OS (HR = 0.44, previous RT 7.9 months vs. no previous RT 17.5 months, p = 0.047, Supplementary Table S1 and Supplementary Figure S2) while age, race and ethnicity, sex, histology, presence of liver or lung metastasis, number of previous lines of systemic therapy (Supplementary Figure S3), and type of ICB combination (Supplementary Figure S4) did not.Sarcoma histology (UPSs vs. other pleomorphic sarcomas) did not have a statistically significant impact on OS (p = 0.90) (Figure 4B).
The best response to ICB treatment per RECIST1.1 significantly impacted OS (p = 0.011) (Figure 5B): the median OS was not attained and 18.6 months in patients whose tumors responded and stabilized per RECIST 1.1, respectively.

Previous Radiation Therapy
Due to the results on the impact of previous radiation therapy, we performed additional analyses to compare patients who had had previous RT and those who did not.While no significant difference was found between these two groups, patients who had previous RT tended to have larger tumors (biggest diameter 7.7 cm vs. 4 cm; Supplementary Table S2).Additionally, we performed a subgroup analysis based on the timing of RT prior to ICB.This analysis showed no difference in PFS or OS based on the timing of RT (peri-operative vs. palliative/metastatic setting, Supplementary Figure S1).

ICB Combination
Due to the results on the impact of ICB combination therapy, we performed additional analyses to compare patients who had standalone ICB therapy and those who did not.Patients who had ICB combinations tended to have more prior surgical resections (median of 2 vs. 1 surgical resections for standalone ICB, p = 0.013) and more prior lines of therapy (median 3 vs. 1, p = 0.062), suggesting that this population was more heavily pretreated.Patients who had ICB combinations also tended to have received ICB as part of a clinical trial (90% of combination ICB vs. 40% of standalone ICB patients; Supplementary Table S3).

Toxicity
No new safety signal was identified, and the toxicity was overall manageable.There were no toxic deaths.Four patients (11%) stopped treatment due to toxicity.Seven patients (19%) experienced > grade 3 toxicities.Five patients (14%) experienced diarrhea or colitis of any grade.

Discussion
This report aims to describe real-world data on ICB treatment for patients with UPSs and other high-grade pleomorphic STSs.While several prospective clinical trials have identified this subtype of STS as one of the most immune-sensitive types of STS [13,14,26], few real-world histology-specific data exist.
The data reported here are overall consistent with that reported in clinical trials with a median PFS of roughly 3 months for UPS patients [13,14]; however, the ORR was slightly inferior to that previously reported, as ours is around 10% versus 20-30% in clinical trials.Real-world data are often slightly less promising than clinical trials, as patients are usually frailer and have more comorbidities and prior lines of treatment.We also found that ICB in later lines of therapy may be less effective and that RECIST response is associated with PFS with ICB treatment, which is consistent with reports across other cancer types [27][28][29][30][31][32][33].
High-grade pleomorphic sarcomas that do not meet all morphologic criteria for UPSs have often been treated along the same lines as UPSs and are offered ICB in clinical practice, and our report indicates that this approach is reasonable for ICB treatment, given that the 3-month PFS and 6-month PFS were 46% and 32%, respectively.Clinical trials are now including these sarcomas with UPS cohorts testing ICB treatment.
The notable difference in our report compared to clinical trials is that combination ICB seemed inferior to standalone ICB regarding PFS.This is not expected, as multiple trials have shown a benefit of combination ICB compared to single-agent PD1 [21,22,34,35].However, a potential selection bias could explain this association since clinicians are aware that single-agent PD1 treatment may take longer to be active and can be concerned with the risk of hyperprogressive disease [36].Thus, in cases of rapidly progressing disease or high tumor burden, clinicians are more likely to try a combination therapy.In contrast, in the case of a slow-growing disease, the added toxicity of a combination therapy is avoided by treating patients with single-agent ICB [37,38].This selection bias is illustrated by the fact that patients who were treated with combination therapies had a higher number of previous surgical resections and lines of systemic therapies, indicating this population was more heavily pretreated and that there is likely a selection bias in this analysis.
The association between RT and ICB response observed in our study is also likely a result of selection bias.The main hypothesis to explain this is that tumors that recurred and progressed despite RT in the peri-operative setting had intrinsically bad biology and an immune-suppressive microenvironment.Likewise, RT in the metastatic setting would be offered in patients with more symptomatic disease, which may inherently be linked to bad biology.However, there may be biological ties, but the role of previous RT in resistance to ICB is controversial.While concurrent ICB and RT are effective and likely synergistic in the treatment of UPSs and other tumor types, previous RT may have a more immune-suppressive role, as several cytokines, including TGFbeta, and tissue remodeling cells, such as macrophages and neutrophils, are recruited to the tumor after RT [39].We tried to investigate differences between patients who had previous RT compared to those who did not and did not find any significant differences in our small cohort.Ultimately, our data are hypothesis-generating in nature, and no strong association or mechanistic claim can be made from our clinical report, but the question of RT timing with respect to ICB may be an important one to address in the future.As such, concurrent RT when feasible with ICB is a very promising therapeutic strategy for patients with UPSs.
This study highlights a critical need for the identification of biomarkers of response to ICB for patients with sarcomas.As our cohort is a small, real-world, heterogeneous cohort, we were unable to identify strong predictors of response.This highlights a challenge in deriving data from real-world studies beyond clinical trials but invites further investigation into potential predictors of response.This is a retrospective, single-center cohort with a small number of patients, and thus, there is significant bias in this analysis, and the statistical power of our findings is limited.The results discussed here are hypothesis-generating and descriptive by nature, and no causality can be inferred.

Conclusions
Real-world retrospective data demonstrate a median PFS of 2.9 months for patients with UPSs and other high-grade pleomorphic sarcomas treated with ICB in the metastatic setting, which is consistent with the published literature.The optimal sequencing of RT and prior lines of systemic therapy needs to be further evaluated.

Supplementary Materials:
The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cancers16091763/s1,Table S1.Overall Survival according to clinical characteristics; Table S2.Patient and disease characteristics by exposure to RT prior to ICB; Table S3.Informed Consent Statement: A waiver of informed consent was used for this study due to this being a retrospective chart review that involves no diagnostic or therapeutic intervention, as well as no direct patient contact.Study staff are unable to obtain consent from study subjects because, due to the international patient population of MD Anderson Cancer Center, it would be impracticable to obtain informed consent from individual patients prior to beginning the protocol.Additionally, it would bias the study if it were restricted to only those patients that we were able to contact.It would not be practicable to conduct this research without this waiver since the status of the patient is unknown, i.e., whether they are alive or deceased, and it is difficult to trace the whereabouts of the patients.

Figure 1 .
Figure 1.Waterfall plot by histology: purple represents UPS, and blue represents othe pleomorphic sarcomas.

Figure 1 .
Figure 1.Waterfall plot by histology: purple represents UPS, and blue represents other pleomorphic sarcomas.

38 *
A total of 33 patients were evaluable for response.

Figure 3 .
Figure 3. Progression-free survival stratified by (A) number of lines of systemic therapy prior to ICB, (B) exposure to radiotherapy (RT) prior to ICB, and (C) type of ICB treatment.

Table 1 .
Patient and disease characteristics.

Table 2 .
Response rates according to clinical characteristics.

Table 3 .
Progression-free survival according to clinical characteristics.
PFS = progression-free survival; ICB = immune checkpoint blockade; HR = hazard ratio; RT = radiotherapy; UPS = undifferentiated pleomorphic sarcoma; (a) multivariate model included previous radiotherapy, number of previous systemic therapies, and type of ICB combination.Values in bold have p-values < 0.05.